TRPV1 is a nonselective cation channel which belongs to the transient receptor potential (TRP) superfamily, contains six transmembrane domains, and has high permeability of calcium ions, and is also called vanilloid receptor 1 (VR1) or capsaicin receptor. As agonists for TRPV1, vanilloids such as capsaicin which is a pungent component in hot chili peppers and resiniferatoxin which is a capsaicin derivative are known. On the other hand, as antagonists for TRPV1, compounds such as iodoresiniferatoxin and capsazepine are known.
TRPV1 is mainly located in sensory neurons, however, it is also expressed in non-neuronal tissues as well as neuronal tissues of epithelium, bone, bladder, gastrointestinal tract, lung, and many other visceral organs.
It is known that TRPV1 is activated by a noxious stimulus such as an acid (pH 5.9 or lower) or heat (43° C. or higher), and physiological effects brought about by activation of TRPV1 are diverse (see Non-patent document 1).
Pain is classified according to the mechanism of onset thereof into nociceptive pain (somatic pain and visceral pain), neuropathic pain (pain caused by nerve damage and occurring without a noxious stimulus), and the like.
Nociceptive pain is pain caused by tissue damage created by a stimulus such as a heat stimulus. Somatic pain is pain caused by activation of nociceptors in cutaneous or deep tissues, and is classified into superficial pain (skin or mucosa origin) and deep pain (muscle, bone, or joint origin). Somatic pain is characterized in that it is localized pain.
As compared with somatic pain, distribution and characteristics of visceral pain are often not clearly identified. It is considered that pain is transmitted through the course of afferent fibers along the autonomic nerves which control the internal organs.
Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself. Neuropathic pain includes intermittent or paroxysmal severe pain as well as tonic pain with burning sensation or the like, and is characterized by accompanied by symptoms such as hypoesthesia, hyperalgesia and allodynia (see Non-patent document 2).
Overactive bladder is a pathological condition with a syndrome including urinary urgency, frequent urination, and urge incontinence. According to the epidemiological survey conducted by The Japan Neurogenic Bladder Society, the prevalence of overactive bladder in Japanese aged 40 years old or older is 12.4% and the total number of patients with overactive bladder is estimated to be about 8.1 million. The prevalence has a high correlation with aging, and the prevalence in those aged 70 years old or older reaches 30% or more. Further, it is shown that the quality of life (QOL) of patients with overactive bladder is remarkably decreased in a wide range including daily life and mental status.
As the cause of overactive bladder, neurogenic causes such as cerebrovascular disorder and spinal cord injury and non-neurogenic causes such as lower urinary tract obstruction are known. However, most cases are idiopathic and the cause of overactive bladder cannot be identified, and it is inferred that several factors are involved in the onset of overactive bladder in combination. The treatment of overactive bladder is mainly drug therapy, and particularly, a muscarinic receptor antagonist is used in the treatment as a first-line drug. However, a satisfactory therapeutic effect cannot be obtained in some patients, and medication compliance sometimes decreases due to discomfort such as dry mouth. Therefore, further development of a therapeutic agent for overactive bladder has been demanded (see Non-patent document 3 and Non-patent document 4).
The gastrointestinal mucosa is a large interface of an individual with the outside world and induces rapid and precise physiological responses to various stimuli and changes in the lumen to maintain the homeostasis thereof. The gastrointestinal tract such as stomach or duodenum is an organ which responds very sensitively to stress. In particular, stomach is exposed not only to mental stress and physical stress such as burn, injury, or surgery but also to many factors to cause mucosal damage including extrinsic factors such as food, alcohol, and drug and intrinsic factors such as gastric acid and bile, and therefore, the stomach is in an environment where mucosal damage is liable to occur.
As a typical intrinsic factor which takes a role in gastric mucosal defense mechanism, prostaglandin is known.
In the treatment of gastrointestinal dysfunction such as gastric ulcer, a compound which suppresses gastric acid secretion such as an H2 receptor inhibitor is used, however, a problem that ulcer relapse occurs when administration is discontinued and the like may sometimes arise (see Non-patent document 5).
Further, it is considered that activation of the sympathetic nervous system by capsaicin via TRPV1 activates energy metabolism, which leads to fat burning, i.e., anti-obesity.
In light of such circumstances, studies have been conducted as to whether compounds having various activities can be applied to a therapeutic agent for a TRPV1-mediated disease, however, the results are not always satisfactory, and further searches for a therapeutic agent for a TRPV1-mediated disease have been demanded.
On the other hand, Patent document 1 describes that a urea derivative which is an active ingredient in the present invention has an inhibitory action on the production of TNF-α and can be used as a therapeutic agent for an autoimmune disease such as rheumatoid arthritis (RA)                Patent document 1: JP-A-2002-53555        Non-patent document 1: Dai, T. and Noguchi, K., Igaku no Ayumi (Journal of Clinical and Experimental Medicine), 2004, Vol. 211, No. 5, pp. 389-392        Non-patent document 2: Igaku no Ayumi (Journal of Clinical and Experimental Medicine), Vol. 195, No. 9, 2000, 582-584, physiological Mechanism of pain generation, Tsunoda, T. and Hanaoka, K.        Non-patent document 3: Guideline for Clinical Evaluation Methods of Drugs for Overactive Bladder (Notification No. 0628001 of the Pharmaceutical Affairs and Food Sanitation Council of the Ministry of Health, Labour and Welfare)        Non-patent document 4: Folia Pharmacologica Japonica, Vol. 229, No. 5, pp. 361-367        Non-patent document 5: Kato, S. et al., G. I. Research, Vol. 13, p. 367, 2005        